Cyclohexyl substituted pyrrolidinones as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1

ABSTRACT

The present invention discloses novel compounds of Formula I: having 11β-HSD type 1 antagonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I, as well as methods of using the compounds and compositions to treat diabetes, hyperglycemia, obesity, hypertension, hyperlipidemia, metabolic syndrome, and other conditions associated with 11β-HSD type 1 activity.

This is the national phase application, under 35 USC 371, forPCT/US2007/067253, filed Apr. 24, 2007, which claims the benefit, under35 USC 119(e), of U.S. provisional application 60/745,442 filed Apr. 24,2006.

This invention relates to compounds that are inhibitors of11-β-hydroxysteroid dehydrogenase type 1 (“11-β-HSD1”), and topharmaceutical compositions thereof, and the uses of these compounds andcompositions in the treatment of the human or animal body, and to novelintermediates useful in preparation of the inhibitors. The presentcompounds show potent and selective inhibition of 11-β-HSD1, and as suchare useful in the treatment of disorders responsive to the modulation of11-β-HSD1, such as diabetes, metabolic syndrome, cognitive disorders,and the like.

Glucocorticoids acting in the liver, adipose tissue, and muscle, areimportant regulators of glucose, lipid, and protein metabolism. Chronicglucocorticoid excess is associated with insulin resistance, visceralobesity, hypertension, and dyslipidemia, which also represent theclassical hallmarks of metabolic syndrome. 11-β-HSD1 catalyses theconversion of inactive cortisone to active cortisol, and has beenimplicated in the development of metabolic syndrome. Evidence in rodentsand humans links 11-β-HSD1 to metabolic syndrome. Evidence suggests thata drug which specifically inhibits 11-β-HSD1 in type 2 diabetic patientswill lower blood glucose by reducing hepatic gluconeogenesis, reducecentral obesity, improve atherogenic lipoprotein phenotypes, lower bloodpressure, and reduce insulin resistance. Insulin effects in muscle willbe enhanced, and insulin secretion from the beta cells of the islet mayalso be increased. Evidence from animal and human studies also indicatesthat an excess of glucocorticoids impair cognitive function. Recentresults indicate that inactivation of 11-β-HSD1 enhances memory functionin both men and mice. The 11-β-HSD inhibitor carbenoxolone was shown toimprove cognitive function in healthy elderly men and type 2 diabetics,and inactivation of the 11-β-HSD1 gene prevented aging-inducedimpairment in mice. Selective inhibition of 11-β-HSD1 with apharmaceutical agent has recently been shown to improve memory retentionin mice.

A number of publications have appeared in recent years reporting agentsthat inhibit 11-β-HSD1. See International Application WO2004/056744which discloses adamantyl acetamides as inhibitors of 11-β-HSD,International Application WO2005/108360 which discloses pyrrolidin-2-oneand piperidin-2-one derivatives as inhibitors of 11-β-HSD, andInternational Application WO2005/108361 which discloses adamantylpyrrolidin-2-one derivatives as inhibitors of 11-β-HSD. In spite of thenumber of treatments for diseases that involve 11-β-HSD1, the currenttherapies suffer from one or more inadequacies, including poor orincomplete efficacy, unacceptable side effects, and contraindicationsfor certain patient populations. Thus, there remains a need for animproved treatment using alternative or improved pharmaceutical agentsthat inhibit 11-β-HSD1 and treat the diseases that could benefit from11-β-HSD1 inhibition. The present invention provides such a contributionto the art based on the finding that a novel class of compounds has apotent and selective inhibitory activity on 11-β-HSD1. The presentinvention is distinct in the particular structures and their activities.There is a continuing need for new methods of treating diabetes,metabolic syndrome, and cognitive disorders, and it is an object of thisinvention to meet these and other needs.

The present invention provides a compound structurally represented byformula I:

or a pharmaceutically acceptable salt thereof, wherein

-   R^(0a) is -halogen;-   R^(0b) is —H or -halogen;-   R¹ is —H, -halogen, —O—CH₃ (optionally substituted with one to three    halogens), or —CH₃ (optionally substituted with one to three    halogens);-   R² is —H, -halogen, —O—CH₃ (optionally substituted with one to three    halogens), or —CH₃ (optionally substituted with one to three    halogens);-   R³ is —H or -halogen;-   R⁴ is    -   —OH, -halogen, —CN, —(C₁-C₄)alkyl(optionally substituted with        one to three halogens), —(C₁-C₆)alkoxy(optionally substituted        with one to three halogens), —SCF₃, —C(O)O(C₁-C₄)alkyl,        —O—CH₂—C(O)NH₂, —(C₃-C₈)cycloalkyl,        —O-phenyl-C(O)O—(C₁-C₄)alkyl, —CH₂-phenyl, —NHSO₂—(C₁-C₄)alkyl,        —NHSO₂-phenyl(R²¹)(R²¹), —(C₁-C₄)alkyl-C(O)N(R¹⁰)(R¹¹),

-   -    wherein the dashed line represents the point of attachment to        the R⁴ position in formula I;

-   R⁵ is    -   —H, -halogen, —OH, —CN, —(C₁-C₄)alkyl(optionally substituted        with 1 to 3 halogens), —C(O)OH, —C(O)O—(C₁-C₄)alkyl,        —C(O)—(C₁-C₄)alkyl, —O—(C₁-C₄)alkyl(optionally substituted with        1 to 3 halogens), —SO₂—(C₁-C₄)alkyl, —N(R⁸)(R⁸),        -phenyl(R²¹)(R²¹),

-   -    wherein the dashed line represents the point of attachment to        the position indicated by R⁵;    -   wherein m is 1, 2, or 3;

-   R⁶ is    -   —H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with        1 to 3 halogens);

-   R⁷ is    -   —H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to        3 halogens);

-   R⁸ is independently at each occurrence    -   —H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or    -   —S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3        halogens);

-   R⁹ is —H or -halogen;

-   R¹⁰ and R¹¹ are each independently    -   —H or —(C₁-C₄)alkyl, or R¹⁰ and R¹¹ taken together with the        nitrogen to which they are attached form piperidinyl,        piperazinyl, or pyrrolidinyl; and

-   R²¹ is independently at each occurrence —H, -halogen, or    —(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens).

The present invention provides compounds of formula I that are useful aspotent and selective inhibition of 11-β-HSD1. The present inventionfurther provides a pharmaceutical composition which comprises a compoundof Formula I, or a pharmaceutical salt thereof, and a pharmaceuticallyacceptable carrier, diluent, or excipient. In addition, the presentinvention provides a method for the treatment of metabolic syndrome, andrelated disorders, which comprise administering to a patient in needthereof an effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides compounds of Formula Ior a pharmaceutically acceptable salt thereof as described in detailabove. While all of the compounds of the present invention are useful,certain of the compounds are particularly interesting and are preferred.The following listings set out several groups of preferred compounds.

In another embodiment the invention provides a compound structurallyrepresented by formula I, or a pharmaceutically acceptable salt thereof,wherein

-   R^(0a) is -halogen; R^(0b) is —H or -halogen;-   R¹ is -halogen; R² is -halogen; R³ is —H or -halogen;-   R⁴ is    -   —OH, -halogen, —CN, —(C₁-C₄)alkyl(optionally substituted with        one to three halogens), —(C₁-C₆)alkoxy(optionally substituted        with one to three halogens), —SCF₃, —C(O)O(C₁-C₄)alkyl,        —O—CH₂—C(O)NH₂, —(C₃-C₈)cycloalkyl,        —O-phenyl-C(O)O—(C₁-C₄)alkyl, —CH₂-phenyl, —NHSO₂—(C₁-C₄)alkyl,        —NHSO₂-phenyl(R²¹)(R²¹), —(C₁-C₄)alkyl-C(O)N(R¹⁰)(R¹¹),

-   -    wherein the dashed line represents the point of attachment to        the R⁴ position in formula I;

-   R⁵ is    -   —H, -halogen, —OH, —CN, —(C₁-C₄)alkyl(optionally substituted        with 1 to 3 halogens), —C(O)OH, —C(O)O—(C₁-C₄)alkyl,        —C(O)—(C₁-C₄)alkyl, —O—(C₁-C₄)alkyl(optionally substituted with        1 to 3 halogens), —SO₂—(C₁-C₄)alkyl, —N(R⁸)(R⁸),        -phenyl(R²¹)(R²¹),

-   -    wherein the dashed line represents the point of attachment to        the position indicated by R⁵;    -   wherein m is 1, 2, or 3;

-   R⁶ is    -   —H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with        1 to 3 halogens);

-   R⁷ is    -   —H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to        3 halogens);

-   R⁸ is independently at each occurrence    -   H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or    -   —S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3        halogens);

-   R⁹ is —H or -halogen;

-   R¹⁰ and R¹¹ are each independently    -   —H or —(C₁-C₄)alkyl, or R¹⁰ and R¹¹ taken together with the        nitrogen to which they are attached form piperidinyl,        piperazinyl, or pyrrolidinyl; and

-   R²¹ is independently at each occurrence —H, -halogen, or    —(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens).

In another embodiment the invention provides a compound structurallyrepresented by formula I, or a pharmaceutically acceptable salt thereof,wherein

-   R^(0a) is -chlorine, -fluorine, or -bromine; R^(0b) is -chlorine,    -fluorine, or -bromine;-   R¹ is -chlorine, -fluorine, or -bromine; R² is -chlorine, -fluorine,    or -bromine; R³ is —H or -halogen;-   R⁴ is    -   —OH, -halogen, —CN, —(C₁-C₄)alkyl(optionally substituted with        one to three halogens), —(C₁-C₆)alkoxy(optionally substituted        with one to three halogens), —SCF₃, —C(O)O(C₁-C₄)alkyl,        —O—CH₂—C(O)NH₂, —(C₃-C₈)cycloalkyl,        —O-phenyl-C(O)O—(C₁-C₄)alkyl, —CH₂-phenyl, —NHSO₂—(C₁-C₄)alkyl,        —NHSO₂-phenyl(R²¹)(R²¹), —(C₁-C₄)alkyl-C(O)N(R¹⁰)(R¹¹),

-   -    wherein the dashed line represents the point of attachment to        the R⁴ position in formula I;

-   R⁵ is    -   —H, -halogen, —OH, —CN, —(C₁-C₄)alkyl(optionally substituted        with 1 to 3 halogens), —C(O)OH, —C(O)O—(C₁-C₄)alkyl,        —C(O)—(C₁-C₄)alkyl, —O—(C₁-C₄)alkyl(optionally substituted with        1 to 3 halogens), —SO₂—(C₁-C₄)alkyl, —N(R⁸)(R⁸),        -phenyl(R²¹)(R²¹),

-   -    wherein the dashed line represents the point of attachment to        the position indicated by R⁵;    -   wherein m is 1, 2, or 3;

-   R⁶ is    -   —H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with        1 to 3 halogens);

-   R⁷ is    -   —H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to        3 halogens);

-   R⁸ is independently at each occurrence    -   —H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or    -   —S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3        halogens);

-   R⁹ is —H or -halogen;

-   R¹⁰ and R¹¹ are each independently    -   —H or —(C₁-C₄)alkyl, or R¹⁰ and R¹¹ taken together with the        nitrogen to which they are attached form piperidinyl,        piperazinyl, or pyrrolidinyl; and

-   R²¹ is independently at each occurrence —H, -halogen, or    —(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens).

In another embodiment the invention provides a compound structurallyrepresented by formula I, or a pharmaceutically acceptable salt thereof,wherein

-   R^(0a) is -chlorine, -fluorine, or -bromine; R^(0b) is -chlorine,    -fluorine, or -bromine;-   R¹ is -chlorine, -fluorine, or -bromine; R² is -chlorine, -fluorine,    or -bromine; R³ is —H or -halogen;-   R⁴ is

-   -    wherein the dashed line represents the point of attachment to        the R⁴ position in formula I;

-   R⁵ is    -   —H, -halogen, —OH, —CN, —(C₁-C₄)alkyl(optionally substituted        with 1 to 3 halogens), —C(O)OH, —C(O)O—(C₁-C₄)alkyl,        —C(O)—(C₁-C₄)alkyl, —O—(C₁-C₄)alkyl(optionally substituted with        1 to 3 halogens), —SO₂—(C₁-C₄)alkyl, —N(R⁸)(R⁸),        -phenyl(R²¹)(R²¹),

-   -    wherein the dashed line represents the point of attachment to        the position indicated by R⁵;    -   wherein m is 1, 2, or 3;

-   R⁶ is    -   —H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with        1 to 3 halogens);

-   R⁷ is    -   —H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to        3 halogens);

-   R⁸ is independently at each occurrence    -   —H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or    -   —S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3        halogens);

-   R⁹ is —H or -halogen;

-   R¹⁰ and R¹¹ are each independently    -   —H or —(C₁-C₄)alkyl, or R¹⁰ and R¹¹ taken together with the        nitrogen to which they are attached form piperidinyl,        piperazinyl, or pyrrolidinyl; and

-   R²¹ is independently at each occurrence —H, -halogen, or    —(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens).

In another embodiment the invention provides a compound structurallyrepresented by formula I, or a pharmaceutically acceptable salt thereof,wherein

-   R^(0a) is -chlorine, -fluorine, or -bromine; R^(0b) is -chlorine,    -fluorine, or -bromine;-   R¹ is -chlorine, -fluorine, or -bromine; R² is -chlorine, -fluorine,    or -bromine; R³ is —H or -halogen;-   R⁴ is

-   -    wherein the dashed line represents the point of attachment to        the R⁴ position in formula I;

-   R⁵ is

-   -   —SO₂—(C₁-C₄)alkyl,    -    wherein the dashed line represents the point of attachment to        the position indicated by R⁵; wherein m is 1, 2, or 3;

-   R⁶ is    -   —H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with        1 to 3 halogens);

-   R⁷ is    -   —H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to        3 halogens);

-   R⁸ is independently at each occurrence    -   —H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or    -   —S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3        halogens);

-   R⁹ is —H or -halogen;

-   R¹⁰ and R¹¹ are each independently    -   —H or —(C₁-C₄)alkyl, or R¹⁰ and R¹¹ taken together with the        nitrogen to which they are attached form piperidinyl,        piperazinyl, or pyrrolidinyl; and

-   R²¹ is independently at each occurrence —H, -halogen, or    —(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens).

In another embodiment the invention provides a compound structurallyrepresented by formula I, or a pharmaceutically acceptable salt thereof,wherein

-   R^(0a) is -chlorine, -fluorine, or -bromine; R^(0b) is -chlorine,    -fluorine, or -bromine;-   R¹ is -chlorine, -fluorine, or -bromine; R² is -chlorine, -fluorine,    or -bromine; R³ is —H or -halogen;-   R⁴ is

-   -    wherein the dashed line represents the point of attachment to        the R⁴ position in formula I;

-   R⁵ is    -   —N(R⁸)(R⁸),

-   -   wherein the dashed line represents the point of attachment to        the position indicated by R⁵;

-   R⁶ is    -   —H, -halogen, —CN, or —(C₁-C₄)alkyl(optionally substituted with        1 to 3 halogens);

-   R⁷ is    -   —H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to        3 halogens); and

-   R⁸ is independently at each occurrence    -   —H, —(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),    -   —C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or    -   —S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3        halogens).

Other embodiments of the invention are provided wherein each of theembodiments described herein above is further narrowed as described inthe following preferences. Specifically, each of the preferences belowis independently combined with each of the embodiments above, and theparticular combination provides another embodiment in which the variableindicated in the preference is narrowed according to the preference.

Preferably embodiments of the invention are structurally represented bythe formula:

wherein R^(0a) is -chlorine, -fluorine, or -bromine. Preferably R^(0b)is -halogen. Preferably R^(0b) is -chlorine, -fluorine, or -bromine.Preferably R^(0a) is -chlorine, or -fluorine, and Preferably R^(0b) is-chlorine or -fluorine. Preferably R^(0a) is -fluorine and R^(0b) is —H.Preferably R^(0a) is -fluorine and R^(0b) is -fluorine. Preferably R¹ is-halogen. Preferably R¹ is —CH₃. Preferably R¹ is -chlorine, -fluorine,or -bromine. Preferably R¹ is -chlorine. Preferably R¹ is -fluorine.Preferably R¹ is -bromine. Preferably R² is -halogen. Preferably R² is—CH₃. Preferably R² is -chlorine, -fluorine, or -bromine. Preferably R²is -chlorine. Preferably R² is -fluorine. Preferably R² is -bromine.Preferably R¹ is -chlorine and R² is -chlorine.Preferably R³ is —H. Preferably R³ is -halogen. Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

Preferably R⁴ is

and R⁶ is —H.Preferably R⁵ is —N(R⁸)(R⁸),

Preferably R⁵ is —SO₂—(C₁-C₄)alkyl,

Preferably R⁵ is chlorine or fluorine. Preferably R⁶ is —H. PreferablyR⁶ is -halogen. Preferably R⁶ is —(C₁-C₄)alkyl(optionally substitutedwith 1 to 3 halogens). Preferably R⁷ is —H. Preferably R⁷ is -halogen,or —(C₁-C₄)alkyl(optionally substituted with 1 to 3 halogens).Preferably R⁷ is -halogen. Preferably R⁷ is —(C₁-C₄)alkyl(optionallysubstituted with 1 to 3 halogens). Preferably R⁸ is independently ateach occurrence —H. Preferably R⁸ is independently at each occurrence—(C₁-C₃)alkyl. Preferably R⁸ is independently at each occurrence —CH₃.Preferably R⁹ is —H. Preferably R⁹ is -halogen. Preferably R⁷ is-fluorine and R⁹ is -fluorine.

A further embodiment of the invention are the novel intermediatepreparations described herein which are useful for preparing the11-β-HSD1 inhibitors according to formula I and the embodimentsdescribed herein.

Patients with type 2 diabetes often develop “insulin resistance” whichresults in abnormal glucose homeostasis and hyperglycemia leading toincreased morbidity and premature mortality. Abnormal glucosehomeostasis is associated with obesity, hypertension, and alterations inlipid, lipoprotein, and apolipoprotein metabolism. Type 2 diabetics areat increased risk of developing cardiovascular complications, e.g.,atherosclerosis, coronary heart disease, stroke, peripheral vasculardisease, hypertension, nephropathy, neuropathy, and retinopathy.Therefore, therapeutic control of glucose homeostasis, lipid metabolism,obesity, and hypertension are important in the management and treatmentof diabetes mellitus. Many patients who have insulin resistance but havenot developed type 2 diabetes are also at risk of developing “SyndromeX” or “Metabolic syndrome”. Metabolic syndrome is characterized byinsulin resistance along with abdominal obesity, hyperinsulinemia, highblood pressure, low HDL, high VLDL, hypertension, atherosclerosis,coronary heart disease, and chronic renal failure. These patients are atincreased risk of developing the cardiovascular complications listedabove whether or not they develop overt diabetes mellitus.

Due to their inhibition of 11-β-HSD1, the present compounds are usefulin the treatment of a wide range of conditions and disorders in whichinhibition of 11-β-HSD1 is beneficial. These disorders and conditionsare defined herein as “diabetic disorders” and “metabolic syndromedisorders”. One of skill in the art is able to identify “diabeticdisorders” and “metabolic syndrome disorders” by the involvement of11-β-HSD1 activity either in the pathophysiology of the disorder, or inthe homeostatic response to the disorder. Thus, the compounds may finduse for example to prevent, treat, or alleviate, diseases or conditionsor associated symptoms or sequelae, of “Diabetic disorders” and“metabolic syndrome disorders”.

“Diabetic disorders” and “metabolic syndrome disorders” include, but arenot limited to, diabetes, type 1 diabetes, type 2 diabetes,hyperglycemia, hyper insulinemia, beta-cell rest, improved beta-cellfunction by restoring first phase response, prandial hyperglycemia,preventing apoptosis, impaired fasting glucose (IFG), metabolicsyndrome, hypoglycemia, hyper-/hypokalemia, normalizing glucagon levels,improved LDL/HDL ratio, reducing snacking, eating disorders, weightloss, polycystic ovarian syndrome (PCOS), obesity as a consequence ofdiabetes, latent autoimmune diabetes in adults (LADA), insulitis, islettransplantation, pediatric diabetes, gestational diabetes, diabetic latecomplications, micro-/macroalbuminuria, nephropathy, retinopathy,neuropathy, diabetic foot ulcers, reduced intestinal motility due toglucagon administration, short bowel syndrome, antidiarrheic, increasinggastric secretion, decreased blood flow, erectile dysfunction, glaucoma,post surgical stress, ameliorating organ tissue injury caused byreperfusion of blood flow after ischemia, ischemic heart damage, heartinsufficiency, congestive heart failure, stroke, myocardial infarction,arrhythmia, premature death, anti-apoptosis, wound healing, impairedglucose tolerance (IGT), insulin resistance syndromes, metabolicsyndrome, syndrome X, hyperlipidemia, dyslipidemia,hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia,arteriosclerosis including atherosclerosis, glucagonomas, acutepancreatitis, cardiovascular diseases, hypertension, cardiachypertrophy, gastrointestinal disorders, obesity, diabetes as aconsequence of obesity, diabetic dyslipidemia, etc. Thus the presentinvention also provides a method of treatment of “Diabetic disorders”and “metabolic syndrome disorders” while reducing and or eliminating oneor more of the unwanted side effects associated with the currenttreatments.

In addition, the present invention provides a compound of Formula I, ora pharmaceutical salt thereof, or a pharmaceutical composition whichcomprises a compound of Formula I, or a pharmaceutical salt thereof, anda pharmaceutically acceptable carrier, diluent, or excipient: for use ininhibiting 11-β-HSD1 activity; for use in inhibiting a 11-β-HSD1activity mediated cellular response in a mammal; for use in reducing theglycemic level in a mammal; for use in treating a disease arising fromexcessive 11-β-HSD1 activity; for use in treating diabetic and othermetabolic syndrome disorders in a mammal; and for use in treatingdiabetes, metabolic syndrome, obesity, hyperglycemia, atherosclerosis,ischemic heart disease, stroke, neuropathy, and wound healing. Thus, themethods of this invention encompass a prophylactic and therapeuticadministration of a compound of Formula I.

The present invention further provides the use of a compound of FormulaI, or a pharmaceutical salt thereof for the manufacture of a medicamentfor inhibiting 11-β-HSD1 activity; for the manufacture of a medicamentfor inhibiting 11-β-HSD1 activity mediated cellular response in amammal; for the manufacture of a medicament for reducing the glycemiclevel in a mammal; for the manufacture of a medicament for treating adisease arising from excessive 11-β-HSD1 activity; for the manufactureof a medicament for treating diabetic and other metabolic syndromedisorders in a mammal; and for the manufacture of a medicament forpreventing or treating diabetes, metabolic syndrome, obesity,hyperglycemia, atherosclerosis, ischemic heart disease, stroke,neuropathy, and improper wound healing.

The present invention further provides a method of treating conditionsresulting from excessive 11-β-HSD1 activity in a mammal; a method ofinhibiting 11-β-HSD1 activity in a mammal; a method of inhibiting a11-β-HSD1 activity mediated cellular response in a mammal; a method ofreducing the glycemic level in a mammal; a method of treating diabeticand other metabolic syndrome disorders in a mammal; a method ofpreventing or treating diabetes, metabolic syndrome, obesity,hyperglycemia, atherosclerosis, ischemic heart disease, stroke,neuropathy, and improper wound healing; said methods comprisingadministering to a mammal in need of such treatment a 11-β-HSD1 activityinhibiting amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition which comprisesa compound of Formula I, or a pharmaceutical salt thereof, and apharmaceutically acceptable carrier, diluent, or excipient.

In addition, the present invention provides a pharmaceutical compositionwhich comprises a compound of Formula I, or a pharmaceutical saltthereof, and a pharmaceutically acceptable carrier, diluent, orexcipient: adapted for use in inhibiting 11-β-HSD1 activity; adapted foruse in inhibiting 11-β-HSD1 activity mediated cellular responses;adapted for use in reducing the glycemic level in a mammal; adapted foruse in treating diabetic and other metabolic syndrome disorders in amammal; and adapted for use in preventing or treating diabetes,metabolic syndrome, obesity, hyperglycemia, atherosclerosis, ischemicheart disease, stroke, neuropathy, and wound healing.

In a further aspect of the invention the present compounds areadministered in combination with one or more further active substancesin any suitable ratios. Such further active substances may for examplebe selected from antidiabetics, antiobesity agents, antihypertensiveagents, agents for the treatment of complications resulting from orassociated with diabetes and agents for the treatment of complicationsand disorders resulting from or associated with obesity. The followinglisting sets out several groups of combinations. It will be understoodthat each of the agents named may be combined with other agents named tocreate additional combinations.

Thus, in a further embodiment of the invention the present compounds maybe administered in combination with one or more antidiabetics.

Suitable antidiabetic agents include insulin, insulin analogues andderivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S),for example N^(εB29)-tetradecanoyl des (B30) human insulin, EP 214 826and EP 705 275 (Novo Nordisk A/S), for example Asp^(B28) human insulin,U.S. Pat. No. 5,504,188 (Eli Lilly), for example Lys^(B28) Pro^(B29)human insulin, EP 368 187 (Aventis), for example Lantus®, GLP-1 andGLP-1 derivatives such as those disclosed in WO 98/08871 (Novo NordiskA/S), as well as orally active hypoglycemic agents.

The orally active hypoglycemic agents preferably comprise imidazolines,sulphonylureas, biguanides, meglitinides, oxadiazolidinediones,thiazolidinediones, insulin sensitizers, insulin secretagogues, such asglimepiride, α-glucosidase inhibitors, agents acting on theATP-dependent potassium channel of the β-cells for example potassiumchannel openers such as those disclosed in WO 97/26265, WO 99/03861 andWO 00/37474 (Novo Nordisk A/S), or mitiglinide, or a potassium channelblocker, such as BTS-67582, nateglinide, glucagon antagonists such asthose disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S andAgouron Pharmaceuticals, Inc.), GLP-1 antagonists, DPP-IV (dipeptidylpeptidase-IV) inhibitors, PTPase (protein tyrosine phosphatase)inhibitors, inhibitors of hepatic enzymes involved in stimulation ofgluconeogenesis and/or glycogenolysis, glucose uptake modulators,activators of glucokinase (GK) such as those disclosed in WO 00/58293,WO 01/44216, WO 01/83465, WO 01/83478, WO 01/85706, WO 01/85707, and WO02/08209 (Hoffman-La Roche) or those disclosed in WO 03/00262, WO03/00267 and WO 03/15774 (AstraZeneca), GSK-3 (glycogen synthasekinase-3) inhibitors, compounds modifying the lipid metabolism such asantilipidemic agents such as HMG CoA inhibitors (statins), compoundslowering food intake, PPAR (Peroxisome proliferator-activated receptor)ligands including the PPAR-alpha, PPAR-gamma and PPAR-delta subtypes,and RXR (retinoid X receptor) agonists, such as ALRT-268, LG-1268 orLG-1069.

In another embodiment, the present compounds are administered incombination with insulin or an insulin analogue or derivative, such asN^(εB29)-tetradecanoyl des (B30) human insulin, Asp^(B28) human insulin,Lys^(B28) Pro^(B29) human insulin, Lantus®, or a mix-preparationcomprising one or more of these.

In a further embodiment of the invention the present compounds areadministered in combination with a sulphonylurea such as glibenclamide,glipizide, tolbautamide, chloropamidem, tolazamide, glimepride,glicazide and glyburide.

In another embodiment of the invention the present compounds areadministered in combination with a biguanide, for example, metformin.

In yet another embodiment of the invention the present compounds areadministered in combination with a meglitinide, for example, repaglinideor nateglinide.

In still another embodiment of the invention the present compounds areadministered in combination with a thiazolidinedione insulin sensitizer,for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone,isaglitazone, darglitazone, englitazone, CS-01/CI-1037 or T 174 or thecompounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation).

In still another embodiment of the invention the present compounds maybe administered in combination with an insulin sensitizer, for example,such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297,GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191, WO00/63192, WO 00/63193 such as ragaglitazar (NN 622 or (−)DRF 2725) (Dr.Reddy's Research Foundation) and WO 00/23425, WO 00/23415, WO 00/23451,WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 63196, WO00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A/S).

In a further embodiment of the invention the present compounds areadministered in combination with an α-glucosidase inhibitor, forexample, voglibose, emiglitate, miglitol or acarbose.

In another embodiment of the invention the present compounds areadministered in combination with an agent acting on the ATP-dependentpotassium channel of the β-cells, for example, tolbutamide,glibenclamide, glipizide, glicazide, BTS-67582 or repaglinide.

In yet another embodiment of the invention the present compounds may beadministered in combination with nateglinide.

In still another embodiment of the invention the present compounds areadministered in combination with an antilipidemic agent orantihyperlipidemic agent for example cholestyramine, colestipol,clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin,pitavastatin, rosuvastatin, probucol, dextrothyroxine, fenofibrate oratorvastin.

In still another embodiment of the invention the present compounds areadministered in combination with compounds lowering food intake.

In another embodiment of the invention, the present compounds areadministered in combination with more than one of the above-mentionedcompounds for example in combination with metformin and a sulphonylureasuch as glyburide; a sulphonylurea and acarbose; nateglinide andmetformin; repaglinide and metformin, acarbose and metformin; asulfonylurea, metformin and troglitazone; insulin and a sulfonylurea;insulin and metformin; insulin, metformin and a sulfonylurea; insulinand troglitazone; insulin and lovastatin; etc.

General terms used in the description of compounds herein described beartheir usual meanings.

As used herein, the terms “(C₁-C₃)alkyl”, “(C₁-C₄)alkyl” or“(C₁-C₆)alkyl” refer to straight-chain or branched-chain saturatedaliphatic groups of the indicated number of carbon atoms, such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, and the like. The term “(C₁-C₆)alkoxy” represents a C₁-C₆ alkylgroup attached through an oxygen and include moieties such as, forexample, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. The term“halogen” refers to fluoro, chloro, bromo, and iodo. The term “(C₃-C₈)cycloalkyl” refers to a saturated or partially saturated carbocycle ringof from 3 to 8 carbon atoms, typically 3 to 7 carbon atoms. Examples of(C₃-C₈) cycloalkyl include but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term “optionally substituted,” or “optional substituents,” as usedherein, means that the groups in question are either unsubstituted orsubstituted with one or more of the substituents specified. When thegroups in question are substituted with more than one substituent, thesubstituents may be the same or different. Furthermore, when using theterms “independently,” “independently are,” and “independently selectedfrom” mean that the groups in question may be the same or different.Certain of the herein defined terms may occur more than once in thestructural formulae, and upon such occurrence each term shall be definedindependently of the other.

It is understood that guinea pigs, dogs, cats, rats, mice, hamsters, andprimates, including humans, are examples of patients within the scope ofthe meaning of the term “patient”. Preferred patients include humans.The term “patient” includes livestock animals. Livestock animals areanimals raised for food production. Ruminants or “cud-chewing” animalssuch as cows, bulls, heifers, steers, sheep, buffalo, bison, goats andantelopes are examples of livestock. Other examples of livestock includepigs and avians (poultry) such as chickens, ducks, turkeys and geese.The patient to be treated is preferably a mammal, in particular a humanbeing.

The terms “treatment”, “treating” and “treat”, as used herein, includetheir generally accepted meanings, i.e., the management and care of apatient for the purpose of preventing, reducing the risk in incurring ordeveloping a given condition or disease, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, delaying, or reversing theprogression or severity, and holding in check and/or treating existingcharacteristics, of a disease, disorder, or pathological condition,described herein, including the alleviation or relief of symptoms orcomplications, or the cure or elimination of the disease, disorder, orcondition. The present method includes both medical therapeutic and/orprophylactic treatment, as appropriate.

As used herein, the term “therapeutically effective amount” means anamount of compound of the present invention that is capable ofalleviating the symptoms of the various pathological conditions hereindescribed. The specific dose of a compound administered according tothis invention will, of course, be determined by the particularcircumstances surrounding the case including, for example, the compoundadministered, the route of administration, the state of being of thepatient, and the pathological condition being treated.

“Composition” means a pharmaceutical composition and is intended toencompass a pharmaceutical product comprising the active ingredient(s)including compound(s) of Formula I, and the inert ingredient(s) thatmake up the carrier. Accordingly, the pharmaceutical compositions of thepresent invention encompass any composition made by admixing a compoundof the present invention and a pharmaceutically acceptable carrier.

The term “substantially pure” refers to pure crystalline form of acompound comprising greater than about 90% of the desired crystallineform, and preferably, greater than about 95% of the desired crystalform.

The term “suitable solvent” refers to any solvent, or mixture ofsolvents, inert to the ongoing reaction that sufficiently solubilizesthe reactants to afford a medium within which to effect the desiredreaction.

The term “unit dosage form” means physically discrete units suitable asunitary dosages for human subjects and other non-human animals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical carrier.

The compounds of the present invention may have one or more chiralcenters and may exist in a variety of stereoisomeric configurations. Asa consequence of these chiral centers the compounds of the presentinvention can occur as racemates, as individual enantiomers or mixturesof enantiomers, as well as diastereomers and mixtures of diastereomers.All such racemates, enantiomers, diastereomers and mixtures are withinthe scope of the present invention, whether pure, partially purified, orunpurified mixtures. For the examples provided herein, when a moleculewhich contains a chiral center or centers of known configuration ispresented, its stereochemistry is designated in the name and in thestructural representation of the molecule. If the stereochemistry isunknown or undefined its stereochemistry is not designated in the nameor in the structural representation of the molecule. Embodiments of theinvention include the Examples provided herein, and although the Exampleprovided may be of one chiral or conformational form, or a salt thereof,further embodiments of the invention include all other stereoisomericand or conformational forms of the examples described, as well aspharmaceutically acceptable salts thereof. These embodiments include anyisolated enantiomers, diastereomers, and or conformers of thesestructures, as well as any mixtures containing more than one form.

Furthermore, when a double bond or a fully or partially saturated ringsystem or more than one center of asymmetry or a bond with restrictedrotatability is present in the molecule diastereomers may be formed. Itis intended that any diastereomers, as separated, pure or partiallypurified diastereomers or mixtures thereof are included within the scopeof the invention. Furthermore, some of the compounds of the presentinvention may exist in different tautomeric forms and it is intendedthat any tautomeric forms which the compounds are able to form areincluded within the scope of the present invention.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or ee which is found using the followingequation:

${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 70:30 is achieved, theee with respect to the first enantiomer is 40%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography with a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the specific stereoisomersand enantiomers of compounds of formula I can be prepared by one ofordinary skill in the art utilizing well known techniques and processes,such as those disclosed by J. Jacques, et al., “Enantiomers, Racemates,and Resolutions”, John Wiley and Sons, Inc., 1981, and E. L. Eliel andS. H. Wilen, “Stereochemistry of Organic Compounds”, (Wiley-Interscience1994), and European Patent Application No. EP-A-838448, published Apr.29, 1998. Examples of resolutions include recrystallization techniquesor chiral chromatography.

The compounds of Formula I, can be prepared by one of ordinary skill inthe art following a variety of procedures, some of which are illustratedin the procedures and schemes set forth below. The particular order ofsteps required to produce the compounds of Formula I is dependent uponthe particular compound to being synthesized, the starting compound, andthe relative ability of the substituted moieties. The reagents orstarting materials are readily available to one of skill in the art, andto the extent not commercially available, are readily synthesized by oneof ordinary skill in the art following standard procedures commonlyemployed in the art, along with the various procedures and schemes setforth below.

The following Schemes, Preparations, Examples and Procedures areprovided to better elucidate the practice of the present invention andshould not be interpreted in any way as to limit the scope of the same.Those skilled in the art will recognize that various modifications maybe made while not departing from the spirit and scope of the invention.All publications mentioned in the specification are indicative of thelevel of those skilled in the art to which this invention pertains.

The optimal time for performing the reactions of the Schemes,Preparations, Examples and Procedures can be determined by monitoringthe progress of the reaction via conventional chromatographictechniques. Furthermore, it is preferred to conduct the reactions of theinvention under an inert atmosphere, such as, for example, argon,nitrogen. Choice of solvent is generally not critical so long as thesolvent employed is inert to the ongoing reaction and sufficientlysolubilizes the reactants to effect the desired reaction. The compoundsare preferably isolated and purified before their use in subsequentreactions. Some compounds may crystallize out of the reaction solutionduring their formation and then collected by filtration, or the reactionsolvent may be removed by extraction, evaporation, or decantation. Theintermediates and final products of Formula I may be further purified,if desired by common techniques such as recrystallization orchromatography over solid supports such as silica gel or alumina.

The skilled artisan will appreciate that not all substituents arecompatible with all reaction conditions. These compounds may beprotected or modified at a convenient point in the synthesis by methodswell known in the art.

The terms and abbreviations used in the instant Schemes, Preparations,Examples and Procedures have their normal meanings unless otherwisedesignated. For example, as used herein, the following terms have themeanings indicated: “psi” refers to pounds per square inch; “TLC” refersto thin layer chromatography; “HPLC” refers to high performance liquidchromatography; “R_(f)” refers to retention factor; “R_(t)” refers toretention time; “δ” refers to part per million down-field fromtetramethylsilane; “MS” refers to mass spectrometry, Observed Massindicates [M+H] unless indicated otherwise. “MS(APCi) refers toatmospheric pressure chemical ionization mass spectrometry, “UV” refersto ultraviolet spectrometry, “¹H NMR” refers to proton nuclear magneticresonance spectrometry. “LCMS” refers to liquid chromatography-massspectrometry, “GC/MS” refers to gas chromatography/mass spectrometry.“IR” refers to infra red spectrometry, and the absorption maxima listedfor the IR spectra are only those of interest and not all of the maximaobserved. “RT” refers to room temperature.

“THF” refers to tetrahydrofuran, “LAH” refers to lithium aluminumhydride, “LDA” refers to lithium diisopropylamide, “DMSO” refers todimethylsulfoxide, “DMF” refers to dimethylforamide, “EtOAc” refers toethyl acetate, “Pd—C” refers to palladium on carbon, “DCM” refers todichloromethane, “DMAP” refers to dimethylaminopyridine, “LiHMDS” refersto Lithium Hexamethyldisilisane, “TFA” refers to trifluoroacetic acid,“EDAC” refers to N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimidehydrochloride, “HOBT” refers to 1-Hydroxy benzotriazole, “Bn-9-BBN”refers to Benzyl-9-borabicyclo[3.3.1]nonane, “Pd(dppf)Cl₂” refers to[1,1′-Bis(diphenylphosphino)ferrocene)dichloropalladium(II), “EDCI”refers to N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride,“DBU” refers to 1,8-Diazabicyclo[5.4.0]undecene-7, “TBSCl” refers totert-butyl-dimethyl-silanyloxymethyl chloride, “NBS” refers toN-Bromosuccinimide, “TsOH” refers to p-toluenesulfonic acid, “DCE”refers to dichloroethane, “DAST” refers to (Diethylamino)sulfurtrifluoride, “EA/H” refers to ethyl acetate/hexanes mixture, “Pd₂(dba)₃”refers to Bis(dibenzylideneacetone)palladium, “BINAP” refers to2,2′-Bis(diphenylphospino-1,1′-binaphthalene, “NMP” refers toN-Methylpyrrollidine, “TMSCN” refers to Trimethylsilyl cyanide, “TBAF”refers to Tetrabutylammonium fluoride, “Tf₂O” refers totrifluoromethanesulfonic anhydride, “TBSO” refers totert-butyl-dimethyl-silanyloxy, “OTf” refers totrifluoromethanesulfonate, MeTi(Oi-Pr)₃ refers to methyltitaniumtriisopropoxide, “BBr₃” refers to boron tribromide, “PBr₃” refers tophosphorous tribromide, “Pd(PPh₃)₄” refers totetrakis(triphenylphoshine)palladium (0), “OAc” refers to acetate, “DME”refers to dimethylethane, “Et₂O” refers to diethyl ether, “(Ph₃P)₄Pd”refers to tetrakis(triphenylphoshine)palladium (0), “DMFDMA” refers toN,N-dimethylformamide dimethyl acetal, “Et₃N” refers to triethylamine,“tBu” refers to t-butyl, “DIPEA” refers to diisopropylethyl amine, “EDC”refers to -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,“HOAc” refers to acetic acid, “boc” refers to t-butoxycarbonyl. In astructure, “Ph” refers to phenyl, “Me” refers to methyl, “Et” refers toethyl, “Bn” refers to benzyl, “MeOH” refers to methanol, “OTf” refers totrifluoromethanesulfonate, “TIPSO” refers to triisopropylsilanyloxy,“TBSO” refers to tert-butyl-dimethyl-silanyloxy.

The Examples provided herein are illustrative of the invention claimedherein and are not intended to limit the scope of the claimed inventionin any way. The preparations and examples are named using AutoNom 2.2 inChemDraw Ultra, or AutoNom 2000 in MDL ISIS/Draw version 2.5 SPI fromMDL Information Systems, Inc., or are provided by Chemical AbstractsServices.

A Varian INOVA 400 MHz spectrometer is used to obtain ¹H NMR Specta thein the solvent indicated. An Agilent HP 1100 instrument equipped with aMass Spectrometer (Agilent MSD SL) is used to obtain LCMS. A WatersXterra C18 (2.1×50 mm, 3.5 micron) is used as stationary phase and astandard method is a gradient of 5-100% acetonitrile/methanol (50:50)with 0.2% ammonium formate over 3.5 minutes then held at 100% B for 0.5minutes at a column temperature of 50° C. and a flow rate of 1.0 mL/min.Another standard method is a gradient of 5-100% acetonitrile/methanol(50:50) with 0.2% ammonium formate over 7.0 minutes then held at 100% Bfor 1.0 minutes at a column temperature of 50° C. and a flow rate of 1.0mL/min. Additional MS analysis via Agilent MSD (loop machine) isstandard Flow injection Analysis (FIA), no column is present and flow is0.5 ml/min of 80% MeOH with 6.5 mM Ammonium Acetate for 30 secs runtime.

In Scheme A, an optionally substituted phenol (1) is protected (e.g.,with TBSCl) to form compound 2, and then compound 2 is converted to thealdehyde (3). Compound 3 is reacted with a compound containing aprotecting group (Pg) and leaving group (Lg) to give the ether compound4. Pg can be —CH₃ or —CH₂-phenyl and Lg can be mesylate or halo.Preferably, the Lg-Pg compound is I—CH₃ or Br—CH₂-phenyl. The aldehydeis reduced to form the alcohol (5) and then converted to compound 6.Preferably, compound 5 is halogenated with PBr₃ to give the2-bromo-methyl compound.

Protection and deprotection of the compounds to form compounds offormula I and others are well known to the skilled artisan and aredescribed in the literature. (For example, see: Greene and Wuts,Protective Groups in Organic Synthesis, Third Edition, John Wiley andSons Inc., 1999).

Scheme B shows the stereo selective synthesis to form the intermediatecompound 10. Compound 8 is formed by acylating commercially available(R)-4-benzyl-oxazolidin-2-one with 4-pentenoyl chloride. It is thenalkylated with an optionally substituted compound 6 (see Scheme A) togive compound of 9. Compound 9 is oxidized to form the aldehydeintermediate compound 10 using ozone and triphenylphosphine or osmiumtetroxide and an oxidant such as sodium metaperiodate.

Preparation 1 2,6-dichloro-4-hydroxy-benzaldehyde

Dissolve 3.5 dichlorophenol (1 kg, 6.13 mol) in 3 L dimethylformamide(DMF) and cool to 0° C. Add imidazole (918.74 g, 6.75 mol), followed bytertbutyldimethylsilyl chloride (1017.13 g, 6.75 mol). Warm the mixtureto room temperature and stir for 15 minutes. Pour into water (6 L) andextract with ether (4 L). Wash the organic layer with water 2 times, 10%aqueous lithium chloride solution then brine before drying over sodiumsulfate. Filter and concentrate under vacuum to obtaintert-butyl-(3,5-dichloro-phenoxy)-dimethyl-silane (1700 g) as an oil.

Dissolve tert-butyl-(3,5-dichloro-phenoxy)-dimethyl-silane (425 g, 1.5mol) in 4 L dry tetrahydrofuran and cool to −68° C. Slowly add 1.1equivalents of sec-butyl lithium (103.1 g, 1.61 mol) at −68° C. (˜1.75hr). After addition is complete stir the reaction at −70° C. for 30 min.Add dimethylformamide (168.5 g, 2.3 mol) and stir the reaction at −70°C. for 1 hr. Add 1 M hydrochloric acid in water (3.5 L) and allow thereaction to warm to room temperature.

Pour the reaction mixture into ether (5 L), wash with water then brine.Dry over sodium sulfate and concentrate under vacuum to an orange solid.Triturate with cold dichloromethane and filter to recover 250 g (80%)pale yellow solid.

Preparation 2 2,6-dichloro-4-methoxy-benzaldehyde

Combine 2,6-dichloro-4-hydroxy-benzaldehyde (120 g, 628.24 mmol) andpotassium carbonate (173.65 g, 1256.5 mmol) in 900 mL dimethylformamideand treat with iodomethane (107 g, 753.9 mmol). Stir the reaction atroom temperature for 3 hours. Filter off solids and pour into 6 L ofwater. Filter solids, wash several times with water, air dry anddissolve in ethyl acetate. Wash with water, followed by brine and thendry over sodium sulfate. Filter and concentrate under vacuum to ˜100 mLvolume, at which point, solids start to crash out. Filter thenconcentrate down the filtrate to yield a second crop. Wash with hexane,combine all solids and vacuum dry to yield 112.3 g of off-white, solid:¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 6.90 (s, 2H), 3.87 (s, 3H).

Preparation 3 2,6-dichloro-4-benzyloxy-benzaldehyde

Treat a mixture of 2,6-dichloro-4-hydroxy-benzaldehyde (250 g, 1.3 mol)and potassium carbonate (361.8 g, 2.62 mol) in 2 L dimethylformamidewith benzyl bromide (268.64 g, 1.57 mol). Stir the reaction at roomtemperature for 1 hour. Filter off solids and pour into 12 L of water.Filter off solid, wash several times with water, air dry and dissolve inethyl acetate. Dry over magnesium sulfate, filter and concentrate undervacuum to ˜1.5 L. Allow to sit overnight then filter. Wash solid withminimal amount of hexane and vacuum dry. Concentrate the filtrate undervacuum and triturate with hexane to yield a second crop of product whichwhen combined with the first crop equals 245 g white crystals. Repeat toobtain a 3rd crop of 80 g as a light-tan powder (88% overall yield): ¹HNMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.43 (m, 5H), 7.28 (s, 2H), 5.25(s, 2H).

Preparation 4 (2,6-dichloro-4-methoxy-phenyl)-methanol

Suspend 2,6-dichloro-4-methoxy-benzaldehyde (112 g, 546 mmol) in 1500 mLethanol and cool in an ice bath to 7° C. Add sodium borohydride (20.67,546 mmol) portionwise to obtain a solution. Remove the ice bath and stirfor 2 hours. Carefully add reaction mixture to saturated ammoniumchloride solution (˜4 L) and stir until fully quenched. Extract withdichloromethane (3×1 L) and dry the combined organic extracts oversodium sulfate. Filter and concentrate under vacuum to yield 113 g of alight-tan solid: ¹H NMR (400 MHz, CDCl₃) δ 6.86 (s, 2H), 4.86 (s, 2H),3.78 (s, 3H), 2.07 (s, 1H).

Preparation 5 (2,6-dichloro-4-benzyloxy-phenyl)-methanol

Prepare the title compound essentially as prepared by the method ofPreparation 4. NMR (DMSO-d₆) δ 7.38 (m, 4H), 7.33 (m, 1H), 7.12 (s, 2H),5.14 (s, 2H), 5.05 (t, 1H), 4.59 (d, 2H).

Preparation 6 2-bromomethyl-1,3-dichloro-5-methoxy-benzene

Dissolve (2,6-dichloro-4-methoxy-phenyl)-methanol (113 g, 545.76 mmol)in 1200 mL dry THF and cool to 0 deg under nitrogen. Add PBr₃ (59.1 g,218.3 mmol) under nitrogen and stir at 0° C. for 30 minutes. Pour intosaturated aqueous NaHCO₃ and extract with EtOAc. Dry and concentrateunder vacuum to obtain 129.4 g product as an off-white solid. NMR(CDCl₃) δ 6.88 (s, 2H), 4.73 (s, 2H), 3.79 (s, 3H).

Preparation 7 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene

Prepare the title compound essentially as prepared by the method ofPreparation 6 in an 89% yield. ES MS (m/z): 347 (M+1).

Preparation 8 (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one

Flush with nitrogen a 12 L 3-neck round bottom flask equipped with amechanical stirrer, internal temperature probe/N₂ inlet, and 1 Laddition funnel for 20 min and then add (R)-4-benzyl-2-oxazolidinone(250 g, 1.41 mol). Dilute with tetrahydrofuran (THF) (1.8 L) and cool ina dry ice/acetone bath until the internal temperature is −74° C.Transfer a 1.6M hexanes solution of n-butyllithium (970 mL, 1.552 mol)to the addition funnel via cannula, and add to the oxazolidinonesolution at a rate such that the internal temperature does not reachabove −65° C. After the addition is complete, allow the reaction to stirin the cooling bath 30 min. Transfer 4-pentenoyl chloride (175 mL, 1.585mol) to the addition funnel and add dropwise to the anion solution overa 25 min period. Stir the reaction for 45 min in the cooling bath.Remove the cooling bath and stir the reaction 18 hr as it slowly reachesroom temperature. Dilute the mixture with 1N aqueous hydrochloric acid(1.5 L) and diethyl ether (1 L). Separate the layers and wash theorganic phase with water (2×1 L) then brine (1 L). Extract the combinedaqueous washes with ether (1 L). Dry the combined organic phases overanhydrous magnesium sulfate, filter, and concentrate to 390 g of a lighttan oil. Purify this material by silica gel chromatography usinghexanes:ethyl acetate to obtain 345 g (94.5%) of a clear, yellow oil.

Preparation 9(R)-4-benzyl-3-[(S)-2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one

Stir a mixture of (R)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one (345 g,1.33 mol) and THF (1.8 L) in a 12 L 3-neck round bottom flask, withinternal temperature probe/nitrogen inlet and addition funnel, under anitrogen atmosphere and cool to −75° C. Transfer 1 M LiHMDS (1.6 L) tothe addition funnel and add at a rate such that the internal temperaturedoes not reach above −60° C. After the addition is complete, allow thereaction to stir at −25° C. for 30 min then cool to about −60° C. Atthis point add solid 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzeneportionwise over 5 min. After the addition is complete, transfer thereaction vessel to a −10° C. acetone bath and maintain the internalreaction temperature below 10° C. for 1 hr. Cool the mixture to 0° C.then quench with 2 L aqueous 1N hydrochloric acid. Transfer the mixtureto a 22 L separatory funnel and dilute with 2.5 L water and 2 L ether.Separate the layers and extract the aqueous layer with ether. Dry thecombined organic phase over anhydrous magnesium sulfate, filter andconcentrate to 800 g of a thick oil. Purify by silica gel chromatographyusing hexanes:ethyl acetate to obtain 597 g, (86%) of a colorless oil.

Preparation 10(R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde

Cool a mixture of(R)-4-benzyl-3-[(S)-2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one(100 g, 190.68 mmol) and dichloromethane (800 mL) to −74° C. Bubbleozone, produced via the A-113 ozone generator at a rate of 75%, throughthe reaction via carrier air at a rate of 5 CFM until the solution takeson a blue color (approx 3 hr). Add triphenylphosphine (60 g, 228.8 mmol)as a solution in 200 mL dichloromethane and allow the reaction to stirwhile reaching room temperature over night. Concentrate the solutionunder vacuum and purify by silica gel chromatography using a gradient of20-50% ethyl acetate in hexanes to obtain 82.1 g (82%) of the product asa white foam: MS (m/z): 526 (M+).

Alternate Procedure for Making(R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde

Treat a mixture of(R)-4-benzyl-3-[(S)-2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one(0.96 g, 1.8 mmol), THF (21 mL) and water (7 mL) with 2.5% osmiumtetroxide in t-butanol (46 mg, 0.18 mmol). Add sodium periodate (1.17 g,5.5 mmol) and stir the reaction 4 hr at room temperature. Quench thereaction with water and extract with ethyl acetate. Wash the organicphase with aqueous 1N sodium thiosulfate then brine. Dry the organiclayer over magnesium sulfate, filter, and concentrate under vacuum.Purify the crude material by silica gel chromatography usinghexanes:ethyl acetate to elute the pure product. Concentrate thefractions containing product under vacuum to afford 0.46 g (48%) ofdesired product. MS (m/z): 526 (M+).

Preparation 11(R)-3-(4-Benzyloxy-2,6-difluoro-benzyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one

Treat a solution of(R)-4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde(4.2 g, 8.0 mmol) and 4,4-Difluorocyclohexylamine hydrochloride (1.4 g,8.4 mmol) in CH₂Cl₂ (100 mL) with HOAc (0.4 mL, 8.0 mmol). The reactionstirs 1 hr at room temperature. Treat the reaction with sodiumtriacetoxyborohydride (6.8 g, 32 mmol) and stir for an additional 4 hrat room temperature. Quench the reaction with water and separate theorganic layer. Wash the organic with brine, dry over MgSO₄, filter, andremove the solvent. Purify the crude by silica gel column chromatographyusing Hexanes:EtOAc to elute the pure product. Remove the solvent toafford 1.8 g (48%) of desired product. MS (m/e): 468 (M+1).

Preparation 12 Trifluoro-methanesulfonic acid3,5-dichloro-4-[(R)-1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenylester

Cool a solution of1-(4,4-Difluoro-cyclohexyl)-3-(2,6-difluoro-4-hydroxy-benzyl)-pyrrolidin-2-one(1.4 g, 3.7 mmol) in pyridine (15 mL) 0° C. and treat withTrifluoromethanesulfonic anhydride (0.9 mL, 5.6 mmol). Allow thereaction to warm to room temperature. After stirring for 2 hr at roomtemperature, quench the reaction with 1N HCl and extract with EtOAc.Wash the organic with brine, dry over MgSO₄, and filter. Remove thesolvent to afford 1.8 g (95%) of desired product. MS (m/e): 510 (M+1).

In Scheme E, compound 11 combines with trans-4-amino-cyclohexanol toform the lactam (17). The 4-hydroxy remains in the trans configurationin compound 17. Compound 17 reacts with methanesulfonyl chloride to formthe trans-4-methanesulfonic acid compound which reacts with TBAF to formthe cis-4-fluoro compound (18).

Preparation 13(R)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one

Mix(R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde(Preparation 10) (3.054 g, 5.8 mmol), trans-4-amino-cyclohexanol (1.35,11.6 mmol), NaBH(OAc)₃ (5.18 g, 23.21 mmol) and acetic acid (0.63 mL,11.2 mmol) in 50 mL of 1,2-dichloroethane. Stir for 12 hours at roomtemperature. Quench with saturated solution of NaHCO₃ and extract withethyl acetate. Wash the extract with brine. Dry over magnesium sulfate,filter, and concentrate. After flash column chromatography receive 1.39g (54%) of the title compound: Mass spectrum (apci) m/z=448 (M+H).

Preparation 14 (R)-trans-Methanesulfonic acid4-[3-(4-benzyloxy-2,6-dichloro-benzyl)-2-oxo-pyrrolidin-1-yl]-cyclohexylester

Dissolve(R)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one(1.291 g, 2.86 mmol) in 25 ml of dry dichloromethane at 0° C. Addtriethylamine (0.73 ml, 5.77 mmol) followed by methanesulfonyl chloride(0.25 ml, 3.17 mmol). Stir at room temperature for 3 hours. Quench with1N HCl and extract with ethyl acetate. Wash the extract with 1N HCl,NaHCO₃ and brine. Dry over magnesium sulfate, filter, and concentrate.Purify by column chromatography to receive 1.315 g of the titlecompound: Mass spectrum (apci) m/z=526 (M+H).

Preparation 15 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one

Dissolve 1,4-dioxaspiro{4.5}decan-8-one (100 g, 640.3 mmol),methyl-4-aminobutyrate hydrochloride (98.5 g, 640.3 mmol), triethylamine(90 mL, 640.3 mmol) and dichloromethane (2 L) and stir at roomtemperature. Add Sodium triacetoxyborohydride (135.7 g, 640.3 mmol) stir17 h at room temperature. Quench with water (1 L), separate, wash theaqueous layer with dichloromethane (3×500 mL), combine the organicphases and dry over anhydrous sodium sulfate, filter and concentrate.Purify the material on a 1.5 kg silica column, 6 inches in diameter, andeluted with 8:2 hexanes/ethyl acetate to 95:5 ethyl acetate/methanol togive 73 g of the title compound as a waxy brown solid. ¹H NMR (CDCl₃) δ3.99-4.10 (m, 1H), 3.93 (s, 4H), 3.32-3.36 (m, 2H), 2.36-2.40 (m, 2H),1.94-2.03 (m, 2H), 1.65-1.83 (m, 8H).

Preparation 163-(2,6-Dichloro-4-methoxy-benzyl)-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one

Cool a solution of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (5g, 22.2 mmol) in tetrahydrofuran (100 mL) to −78° C. under nitrogenpurge. Add LDA (2.0 M, 15 mL, 30 mmol) at a rate such that the internalreaction temperature did not reach above −67° C. Stir 30 min at −78° C.,add a solution of 2-bromomethyl-1,3-dichloro-5-methoxy-benzene, 6.6 g,24.4 mmol) in tetrahydrofuran (20 mL) over a 1-2 minute period, removethe cold bath and allow reaction to warm over 3 hr. Quench the reactionwith saturated aqueous ammonium chloride (100 mL), extract with ethylacetate (3×100 mL), combine the extracts and dry over anhydrous sodiumsulfate. Purify on silica column eluting with 8:2 hexanes:ethyl acetateto 1:1 hexanes:ethyl acetate to afford the product as a ivory solid, 6.5g, 71%. ¹H NMR (CDCl₃) δ 6.86 (s, 2H), 4.06-4.12 (m, 1H), 3.94 (s, 4H),3.77 (s, 3H), 3.32-3.41 (m, 2H), 3.15-3.21 (m, 1H), 2.83-2.97 (m, 2H),1.68-2.04 (m, 8H). LCMS (m+1) 414.

Preparation 173-(2,6-Dichloro-4-methoxy-benzyl)-1-(4-oxo-cyclohexyl)-pyrrolidin-2-one

Dissolve3-(2,6-Dichloro-4-methoxy-benzyl)-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one(6.5 g, 15.7 mmol) in acetone (100 mL), add p-toluenesulfonic acidhydrate (3 g, 15.7 mmol) and stir for 24 hr at room temp. Add 5Nhydrochloric acid (10 mL) heat to 45° C. for 1 hr. Reaction progress canbe monitored by TLC. Concentrate the reaction mixture, dilute withsaturated aqueous sodium hydrogen carbonate (500 mL) and extract withethyl acetate (3×150 mL). Wash the combined extracts with water (100 mL)and brine (100 mL), dry over anhydrous sodium sulfate, filter, andconcentrate to about 50 mL volume, dilute with hexanes (50 mL) andfilter to give 5.5 g, 95%, as a white solid. ¹H NMR (CDCl₃) δ 6.78 (s,2H), 4.44-4.52 (m, 1H), 3.78 (s, 3H), 3.37-3.47 (m, 1H), 3.29-3.36 (m,1H), 3.15-3.23 (m, 2H), 2.39-2.62 (m, 4H), 1.80-2.11 (m, 6H). LCMS (m+1)370.

Preparation 183-(2-Chloro-4-methoxy-benzyl)-1-(4-fluoro-cyclohex-3-enyl)-pyrrolidin-2-one

Dissolve3-(2,6-Dichloro-4-methoxybenzyl)-1-(4-oxocyclohexyl)-pyrrolidin-2-one(Preparation 17) (2.09 g, 5.4 mmol) in dichloromethane (50 mL) andethanol (0.06 mL, 1.08 mmol) and cool to 0° C. Add deoxo-fluor (1.69 mL,9.18 mmol) over several minutes. Stir overnight at room temperature. Addsaturated sodium bicarbonate and extract aqueous layer withdichloromethane. Wash the organic layer with brine and dry with Na₂SO₄,filter and concentrate to dryness. Purify the crude mixture over silicagel (4/1 hexane in ethyl acetate) to give 650 mg (32%) of the titlecompound: mass spectrum (m/e): 374 (M+1).

In Scheme G, the lactam (24) in the cis configuration reacts with TBAFto form the 4-hydroxy compound (25) which remains in the cisconfiguration. Compound 25 reacts with DAST to form the trans-4-fluorocompound (26). The alkylation step results in the trans-F-cyclohexylcompound (27).

Preparation 19 1-(trans-4-hydroxy-cyclohexyl)-pyrrolidin-2-one

Add trans-4-aminocyclohexanol (230 g, 2.0 mol) to γ-butyrolactone (140mL, 1.82 mol) in a 1 L round-bottom flask equipped with large magneticstirrer, thermometer and condenser/nitrogen bubbler. Heat the mixture at190° C. for 68 hours. Cool to ambient temperature and mix with water (1L). Extract into dichloromethane (10×1.5 L). Dry the extracts overmagnesium sulfate, filter and evaporate to a brown solid. Triturate withdiethyl ether to afford 144.7 g (43%) of the title compound: MS (m/z):184 (M+1).

Preparation 20 cis-4-nitro-benzoic acid4-(2-oxo-pyrrolidin-1-yl)-cyclohexyl ester

Dissolve 1-(trans-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (144 g, 0.79mol) in dry tetrahydrofuran (5 L) and cool to −5° C. under nitrogen. Addtriphenylphosphine (310 g, 1.185 mol) and 4-nitrobenzoic acid (198 g,1.185 mol). Add diisopropyl azodicarboxylate (230 mL, 1.185 mol)drop-wise and stir at room temperature overnight. Add saturated aqueoussodium bicarbonate (1 L) and extract into dichloromethane (2×2.5 L) in a20 L separating funnel. Dry the combined organic layers over magnesiumsulfate, filter and concentrate. Purify over silica gel(iso-hexane/ethyl acetate 50-100% then 10% methanol in ethyl acetate) toafford 163 g (62%) of the title compound.

Preparation 21 cis-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one

Dissolve cis-4-nitro-benzoic acid 4-(2-oxo-pyrrolidin-1-yl)-cyclohexylester (87.9 g, 264 mmol) in methanol (1.35 L) and water (150 mL) andtreat with potassium carbonate (109.5 g, 800 mmol). Stir at roomtemperature overnight to give a white precipitate. Evaporate to dryness.Remove excess water by mixing with ethanol and concentrating to drynessunder vacuum. Repeat this procedure. Stir in tetrahydrofuran (1 L) for 1hour then filter. Evaporate the filtrate to an oil and crystallize fromdiethyl ether (100 mL) to afford 40 g (83%) of the title compound.

Preparation 22cis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one

Dissolve cis-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (40 g, 220 mmol)in dry dichloromethane (1 L). Add imidazole (22.5 g, 330 mmol) followedby tert-butyldimethylsilyl chloride (50 g, 330 mmol). Stir undernitrogen at room temperature overnight. Wash with water (250 mL) andsaturated aqueous sodium bicarbonate (250 mL). Dry over magnesiumsulfate, filter and evaporate to an oil. Pass through a silica gel padwith iso-hexane/ethyl acetate (0-50%) to afford 51 g (79%) the titlecompound as a clear, pale-yellow oil: MS (m/z): 298 (M+1).

Preparation 23 cis-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one

Heat a solution ofcis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one(500 mg) in 5 mL of 1N HCl in EtOH to 45° C. for 1 h. Cool the mixtureto room temp and concentrate. Dissolve the residue in NaHCO₃ (10 mL) andCH₂Cl₂ (10 mL). Extract the aqueous layer two times with 10 mL ofCH₂Cl₂. Dry the organic layer over Na₂SO₄, filter and concentrate.Purify the crude material by chromatography to yield the title compound:mass spectrum (m/z): 184 (M+1).

Preparation 24 trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one

To a solution of cis-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one in CH₂Cl₂at −30° C., add 786 mL of DAST dropwise. Allow the resulting mixture towarm up to room temp and let stand for 1 h. To the solution, add 10 mLof 5% aq NaHCO₃ and allow to stand at room temp for 1 h. Extract theaqueous layer by CH₂Cl₂ twice (2×10 mL) and then dry the organic layerover Na₂SO₄, filter and concentrate. Purify the crude material bychromatography to yield the title compound: mass spectrum (m/z): 186(M+1).

In Scheme H, trans-4-amino-cyclohexanol reacts with compound 29 to formthe lactam (30) in the trans configuration. Compound 30 reacts with DASTto form cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one (31). In thealkylation step, the cis configuration is retained and results in thecis-F-cyclohexyl compound (32).

Preparation 25 trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one

Heat a mixture of trans-4-amino-cyclohexanol (7.36 g, 63.89 mmol) anddihydro-furan-2-one (5 g, 58.08 mmol), in neat, up to 190° C. for 68 h.Cool the mixture to room temp. Dissolve the residue in water and extractwith CH₂Cl₂ (5×100 mL). Dry the organic layer over Na₂SO₄, filter andconcentrate. Purify the crude material by chromatography to afford thetitle compound: mass spectrum (m/z): 184 (M+1).

Preparation 26 cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one

To a solution of trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (3.2 g)in CH₂Cl₂ (10 mL) at −30° C., add 2.75 mL of DAST dropwise. Allow theresulting mixture to warm up to room temp and stand for 1 h. To thesolution, add 10 mL of 5% aq NaHCO₃ and allow to stand at room temp for1 h. Extract the aqueous layer by CH₂Cl₂ twice (2×10 mL). Dry theorganic layer over Na₂SO₄, filter and concentrate. Purify the crudematerial by chromatography to yield 2.05 g of the title compound: massspectrum (m/z): 186 (M+1).

In Scheme I, either the cis ortrans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one reacts with compound 34to form the dichloro phenyl ester (35). If 33 is the cis compound, then35 will be cis and if 33 is the trans compound, then 35 is trans. Thecis compound (35) reacts with pyridine boronic acid to form the ciscompound (36), and trans compound (35) reacts with pyridine boronic acidto form the trans compound (36).

Preparation 27 trifluoro-methanesulfonic acid3,5-dichloro-4-[cis-1-(4-fluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenylester

To a solution of cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one (252 mg,1.36 mmol) in 13 mL dry THF, add 1.09 mL of 2M LDA (1.2 eq.) in THFdropwise at −78° C. Then, add 821 mg of trifluoro-methanesulfonic acid3,5-dichloro-4-methanesulfonyloxymethyl-phenyl ester (1.5 eq) at −78° C.Allow the resulting solution to stand at room temp for overnight. Quenchthe mixture with saturated aqueous NH₄Cl and extract with CH₂Cl₂. Washthe organic layer with water, then brine, and dry over Na₂SO₄, filterand concentrate. Purify the crude material by chromatography to affordthe title compound: mass spectrum (m/z): 358 (M+1).

Preparation 28 trifluoro-methanesulfonic acid3,5-dichloro-4-[trans-1-(4-fluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenylester

To a solution of trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one (252 mg,1.36 mmol) in 13 mL dry THF, add 1.09 mL of 2M LDA (1.2 eq.) in THFdropwise at −78° C. Then, add 821 mg of trifluoro-methanesulfonic acid3,5-dichloro-4-methanesulfonyloxymethyl-phenyl ester (1.5 eq) at −78° C.Allow the resulting solution to stand at room temp for overnight. Quenchthe mixture with saturated aqueous NH₄Cl and extract with CH₂Cl₂. Washthe organic layer with water, then brine, and dry over Na₂SO₄, filterand concentrate. Purify the crude material by chromatography to affordthe title compound: mass spectrum (m/z): 358 (M+1).

Preparation 29 (4,4-difluoro-cyclohexyl)-carbamic acid tert-butyl ester

Allow the solution of (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester(1 g, 4.69 mmol), 1.76 g of Deoxofluor (7.97 mmol) and 53 μL of EtOH in16 mL of CH₂Cl₂ to stand at room temp for 16 hr. Quench the reactionwith NaHCO₃. Wash the organic layer with NaCl, then NaHCO₃, and dry overNa₂SO₄, filter and concentrate. Purify the crude material bychromatography to afford the title compound: mass spectrum (m/z): 236(M+1).

Preparation 30 4,4-difluoro-cyclohexylamine

Allow the solution of (4,4-difluoro-cyclohexyl)-carbamic acid tert-butylester in 20 mL of TFA to stand at room temp for overnight. Concentratethe mixture under vacuum. Pass the residue through a SCX column to yield251 mg of the title product: mass spectrum (m/z): 136 (M+1).

Preparation 31 4-chloro-N-(4,4-difluoro-cyclohexyl)-butyramide

To a solution of 4,4-difluoro-cyclohexylamine (295 mg) and Et₃N (0.91mL) in 22 mL of CH₂Cl₂, add 4-chloro-butyryl chloride (0.42 g). Allowthe resulting mixture to stand at room temp for 4 hr. Remove the organicsolvent under vacuum. Dissolve the residue in Et₂O. Wash the organiclayer with 1N HCl, then brine, and then H₂O, and dry over Na₂SO₄, filterand concentrate. Purify the crude material by chromatography to afford0.41 g of the title compound: mass spectrum (m/z): 240 (M+1).

Preparation 32 1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one

Heat the mixture of 4-chloro-N-(4,4-difluoro-cyclohexyl)-butyramide(0.41 g, 1.7 mmol) and 0.69 g of NaH in 17 mL of THF to 70° C. forovernight. Dilute the reaction mixture with Et₂O. Filter the precipitatethrough a pad of celite. Wash the organic layer with saturated aqueousNaCl, dry over Na₂SO₄, filter and concentrate. Purify the crude materialby chromatography to afford 0.19 g of the title compound: mass spectrum(m/z): 204 (M+1).

Preparation 33 trifluoro-methanesulfonic acid3,5-dichloro-4-[1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenylester

To a solution of 1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one (447 mg,2.2 mmol) in 22 mL dry THF, add 1.76 mL of 2M LDA (1.2 eq.) in THFdropwise at −78° C. Then, add 1.24 g of trifluoro-methanesulfonic acid3,5-dichloro-4-methanesulfonyloxymethyl-phenyl ester (1.4 eq) at −78° C.Allow the resulting solution to stand at room temp for overnight. Quenchthe mixture with saturated aqueous NH₄Cl and extract with CH₂Cl₂. Washthe organic layer with water, then brine, and dry over Na₂SO₄, filterand concentrate. Purify the crude material by chromatography to affordthe title compound: mass spectrum (m/z): 376 (M+1).

Preparation 34 4-Bromo-1-bromomethyl-2-chloro-benzene

Dissolve 4-bromo-2-chloro-1-methyl-benzene (64.3 g, 312.9 mmol) incarbon tetrachloride (1 L). Add benzoyl peroxide (760 mg, 3.1 mmol) andN-bromosuccinamide (58.5 g, 329 mmol) and heat to 80° C. for 18 hours.Cool reaction to room temperature and filter. Concentrate the filtrateand purify by silica gel (hexanes) to yield 63 g (71%) of the titlecompound. NMR (CDCl₃) δ 7.57 (d, 1H), 7.39 (dd, 1H), 7.31 (d, 1H), 4.53(s, 2H).

EXAMPLE 1(R)-3-(2,6-Dichloro-4-hydroxy-benzyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one

Treat a solution of(R)-3-(4-Benzyloxy-2,6-difluoro-benzyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one(1.8 g, 3.8 mmol) in EtOAc (30 mL) with Palladium Hydroxide on carbon(0.2 g) and purge the solution with Hydrogen. Stir the reactionovernight under 1 atm of hydrogen. Filter the reaction through celite toremove catalyst. Remove the solvent to afford 1.4 g (97%) of desiredproduct. MS (m/e): 378 (M+1).

EXAMPLE 23′,5′-Dichloro-4′-[(R)-1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylicacid methyl ester

Treat a solution of Trifluoro-methanesulfonic acid3,5-dichloro-4-[(R)-1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenylester (Preparation 12) (1.8 g, 3.5 mmol), 4-Methoxycarbonylphenylboronicacid (1.3 g, 7.0 mmol), and Tetrakis(triphenylphosphine)palladium(0)(0.4 g, 0.4 mmol) in DME (20 mL) with 2M aqueous K₂CO₃ (5.2 mL). Heatthe reaction to 80° C. and stir overnight. Cool the reaction and quenchwith 1N HCl. Extract the aqueous with EtOAc. Wash the organic withbrine, dried over MgSO₄, and filter. Purify the crude by silica gelcolumn chromatography using Hexanes:EtOAc to elute the pure product.Remove the solvent to afford 1.0 g (57%) of desired product. MS (m/e):498 (M+1).

TABLE 1 Prepare the Examples of Table 1 essentially by the method ofExample 2 except that 4-methoxycarbonylphenylboronic acid is replaced bythe reagent as indicated in column 3. Data Example Structure andChemical name Reagent m/z (M + 1) 3

4-fluorophenyl boronic acid MS (m/z): 456 (M + 1).(R)-3-(3,5-Dichloro-4′-fluoro- biphenyl-4-ylmethyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2- one 4

4-chlorophenyl boronic acid MS (m/z): 472 (M + 1).(R)-1-(4,4-Difluoro-cyclohexyl)-3- (3,5,4′-trichloro-biphenyl-4-ylmethyl)-pyrrolidin-2-one 5

4-(trifluoromethoxy)- phenyl boronic acid MS (m/z): 522 (M + 1).(R)-3-(3,5-Dichloro-4′- trifluoromethoxy-biphenyl-4-ylmethyl)-1-(4,4-difluoro- cyclohexyl)-pyrrolidin-2-one 6

1-methyl-4-(4,4,5,5- tetramethyl-1,3,2- dioxaborolan-2-yl)- 1H-pyrazoleMS (m/z): 442 (M + 1). (R)-3-[2,6-Dichloro-4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-1-(4,4- difluoro-cyclohexyl)-pyrrolidin-2- one

EXAMPLE 73′,5′-Dichloro-4′-[(R)-1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylicacid

Treat a solution of3′,5′-dichloro-4′-[(4,4-Difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylicacid methyl ester (1.0 g, 2.0 mmol) in THF/water (15 mL/5 mL) with 2Maqueous LiOH (3.0 mL). Stir the reaction overnight at room temperature.Quench the reaction with 1N HCl and extract with EtOAc. Wash the organicwith brine, dry over MgSO₄, and filter. Remove the solvent to afford0.97 g (100%) of desired product. MS (m/e): 482 (M+1).

EXAMPLE 8(R)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one

Dissolve TBAF.3H₂O (1.595 g, 1.30 mmol) in 10 ml of acetonitrile. Addwater (0.18 ml, 9.91 mmol) and stir for 10 minutes. Add(R)-trans-Methanesulfonic acid4-[3-(4-benzyloxy-2,6-dichloro-benzyl)-2-oxo-pyrrolidin-1-yl]-cyclohexylester (Preparation 14) (1.30 g, 2.48 mmol). Stir at 80° C. for 12 hours.Quench with saturated NaHCO₃ and extract with ethyl acetate. Wash theextract with brine. Dry over magnesium sulfate, filter, and concentrate.After flash column chromatography receive 0.230 g (21%) of the titlecompound: Mass spectrum (apci) m/z=450 (M+H).

EXAMPLE 93-(2,6-Dichloro-4-methoxy-benzyl)-trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one

Dissolve3-(2-Chloro-4-methoxy-benzyl)-1-(4-fluoro-cyclohex-3-enyl)-pyrrolidin-2-one(Preparation 18) (0.650 g, 1.75 mmol) in tetrahydrofuran (15 mL) and addpalladium hydroxide on carbon 20 wt. % (0.109 g, 0.774 mmol). Stir thereaction mixture under hydrogen for 5 hours and concentrate underreduced pressure to dryness. Purify the residue over silica gel, (4/1 to3/1 hexane in ethyl acetate) to give 0.257 g (39%) of the titlecompound: mass spectrum (m/z): 375 (M+1).

EXAMPLE 103-(4-Bromo-2-chloro-benzyl)-trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one

To a solution of trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one(Preparation 24) (20 mg, 0.11 mmol) in 3 mL dry THF, add 0.165 mL of 2MLDA (1.5 eq.) in THF dropwise at −78° C. Then, add 16 mg of4-Bromo-1-bromomethyl-2-chloro-benzene (2 eq) at −78° C. Allow theresulting solution to stand at room temp for overnight. Quench themixture with saturated aqueous NH₄Cl and extract with CH₂Cl₂. Wash theorganic layer with water, brine, dry over Na₂SO₄, filter andconcentrate. Purify the crude material by chromatography to afford 10.5mg of the title compound: mass spectrum (m/z): 389 (M+1).

EXAMPLE 113-(4-Bromo-2-chloro-benzyl)-cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one

To a solution of cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one(Preparation 26) (190 mg, 1.03 mmol) in 5 mL dry THF, add 1.29 mL of 2MLDA (2.5 eq.) in THF dropwise at −78° C. Then, add 16 mg of4-Bromo-1-bromomethyl-2-chloro-benzene (2 eq) at −78° C. Allow theresulting solution to stand at room temp for overnight. Quench themixture with saturated aqueous NH₄Cl and extract with CH₂Cl₂. Wash theorganic layer with water, brine, dry over Na₂SO₄, filter andconcentrate. Purify the crude material by chromatography to afford thetitle compound: mass spectrum (m/z): 389 (M+1).

EXAMPLE 123-(2,6-Dichloro-4-pyridin-3-yl-benzyl)-cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one

Heat a solution of trifluoro-methanesulfonic acid3,5-dichloro-4-[cis-1-(4-fluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenylester (Preparation 27) (0.346 g, 0.705 mmol), pyridine-3-boronic acid(0.173 g, 1.41 mmol), Pd(PPh₃)₄ (81 mg), 7 mL of 0.1 M Na₂CO₃ aqsolution in 7 mL of dimethoxy ethane at 80° C. for 24 h. Cool themixture to room temp and quench with 20 mL of 1N HCl. Dilute the mixturewith 20 mL of EtOAc. Wash the organic layer with water, brine and dryover Na₂SO₄, filter and concentrate. Purify the crude material bychromatography to afford the title compound: mass spectrum (m/z): 421(M+1).

EXAMPLE 133-(2,6-Dichloro-4-pyridin-3-yl-benzyl)-trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one

Heat a solution of trifluoro-methanesulfonic acid3,5-dichloro-4-[trans-1-(4-fluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenylester (Preparation 28) (0.346 g, 0.705 mmol), pyridine-3-boronic acid(0.173 g, 1.41 mmol), Pd(PPh₃)₄ (81 mg), 7 mL of 0.1 M Na₂CO₃ aqsolution in 7 mL of dimethoxy ethane at 80° C. for 24 h. Cool themixture to room temp and dilute with 20 mL of 1N NaHCO₃. Dilute themixture with 20 mL of EtOAc. Wash the organic layer with water, brineand dry over Na₂SO₄, filter and concentrate. Purify the crude materialby chromatography to afford the title compound: mass spectrum (m/z): 421(M+1).

EXAMPLE 143-(4-Bromo-2-chloro-benzyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one

To a solution of 1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one (190 mg,0.94 mmol) in 10 mL dry THF, add 1.04 mL of 1.5M LDA (1.5 eq.) in hexanedropwise at −78° C. Then, add 0.59 g of4-bromo-1-bromomethyl-2-chloro-benzene (1.5 eq) at −78° C. Allow theresulting solution to stand at room temp for overnight. Quench themixture with saturated aqueous NaCl and extract with Et₂O. Wash theorganic layer with water, then brine, and dry over Na₂SO₄, filter andconcentrate. Purify the crude material by chromatography to afford thetitle compound: mass spectrum (m/z): 407 (M+1).

EXAMPLE 153-(2,6-Dichloro-4-pyridin-3-yl-benzyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one

Heat a solution of trifluoro-methanesulfonic acid3,5-dichloro-4-[1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenylester (Preparation 33) (0.585 g, 1.15 mmol), pyridine-3-boronic acid(0.283 g, 2.30 mmol), Pd(PPh₃)₄ (133 mg), 11.5 mL of 0.1 M Na₂CO₃ aqsolution in 11.5 mL of dimethoxy ethane at 80° C. for 24 hr. Cool themixture to room temp and dilute with 20 mL of 1N NaHCO₃. Dilute themixture with 20 mL of EtOAc. Wash the organic layer with water, thenbrine, and dry over Na₂SO₄, filter and concentrate. Purify the crudematerial by chromatography to afford the title compound: mass spectrum(m/z): 439 (M+1).

In the following section enzyme and functional assays are describedwhich are useful for evaluating the compounds of the invention.

11β-HSD Type 1 Enzyme Assay

Human 11β-HSD type 1 activity is measured by assaying NADPH productionby fluorescence assay. Solid compounds are dissolved in DMSO to aconcentration of 10 mM. Twenty microliters of each are then transferredto a column of a 96-well polypropylene Nunc plate where they are furtherdiluted 50-fold followed by subsequent two-fold titration, ten timesacross the plate with additional DMSO using a Tecan Genesis 200automated system. Plates are then transferred to a Tecan Freedom 200system with an attached Tecan Temo 96-well head and an Ultra 384 platereader. Reagents are supplied in 96-well polypropylene Nunc plates andare dispensed individually into black 96-well Molecular Devices HighEfficiency assay plates (40 μL/well capacity) in the following fashion:9 μL/well of substrate (2.22 mM NADP, 55.5 μM Cortisol, 10 mM Tris,0.25% Prionex, 0.1% Triton ×100), 3 μL/well of water to compound wellsor 3 μL to control and standard wells, 6 μL/well recombinant human11β-HSD type 1 enzyme, 2 μL/well of compound dilutions. For ultimatecalculation of percent inhibition, a series of wells are added thatrepresent assay minimum and maximum: one set containing substrate with667 μM carbenoxolone (background), and another set containing substrateand enzyme without compound (maximum signal). Final DMSO concentrationis 0.5% for all compounds, controls and standards. Plates are thenplaced on a shaker by the robotic arm of the Tecan for 15 seconds beforebeing covered and stacked for a three hour incubation period at roomtemperature. Upon completion of this incubation, the Tecan robotic armremoves each plate individually from the stacker and places them inposition for addition of 5 μL/well of a 250 μM carbenoxolone solution tostop the enzymatic reaction. Plates are then shaken once more for 15seconds then placed into an Ultra 384 microplate reader (355EX/460EM)for detection of NADPH fluorescence.

Data for example compounds in the 11-βHSD1 assay are shown below:

Human 11-βHSD1 IC₅₀ Example Structure (nM) 3

364 6

302 10

250 11

446 12

260

Compounds of the invention can also tested for selectivity against11-βHSD2 in an assay similar to that described for 11-βHSD1, but usingthe 11-βHSD2 enzyme. The assay using the 11-βHSD2 enzyme can be carriedout by the methods described herein and supplemented by methods known inthe art.

Human Aortic Smooth Muscle Cell Assay

Primary human aortic smooth muscle cells (AoSMC) are cultured in 5% FBSgrowth medium to a passage number of 6, then pelleted by centrifugationand resuspended at a density of 9×10⁴ cells/mL in 0.5% FBS assay mediumcontaining 12 ng/mL hTNFα to induce expression of 11β-HSD1. Cells areseeded into 96-well tissue culture assay plates at 100 μL/well (9×10³cells/well) and incubated for 48 hours at 37° C., 5% CO₂. Followinginduction, cells are incubated for 4 hours at 37° C., 5% CO₂ in assaymedium containing test compounds then treated with 10 μL/well of 10 μMcortisone solubilized in assay medium, and incubated for 16 hours at 37°C., 5% CO₂. Medium from each well is transferred to a plate forsubsequent analysis of cortisol using a competitive fluorescenceresonance time resolved immunoassay. In solution, an allophycocyanin(APC)-cortisol conjugate and free cortisol analyte compete for bindingto a mouse anti-cortisol antibody/Europium (Eu)-anti mouse IgG complex.Higher levels of free cortisol result in diminishing energy transferfrom the Europium-IgG to the APC-cortisol complex resulting in less APCfluorescence. Fluorescent intensities for Europium and APC are measuredusing a LJL Analyst AD. Europium and APC excitation is measured using360 nm excitation and 615 nm and 650 nm emission filters respectively.Time resolved parameters for Europium were 1000 μs integration time witha 200 μs delay. APC parameters are set at 150 μs integration time with a50 μs delay. Fluorescent intensities measured for APC are modified bydividing by the Eu fluorescence (APC/Eu). This ratio is then used todetermine the unknown cortisol concentration by interpolation using acortisol standard curve fitted with a 4-parameter logistic equation.These concentrations are then used to determine compound activity byplotting concentration versus % inhibition, fitting with a 4-parametercurve and reporting the IC₅₀.

All of the examples disclosed herein demonstrate activity in the humanaortic smooth muscle cell assay with IC₅₀ of less than 300 nM. Data forexample compounds in the human aortic smooth muscle cell assay are shownbelow:

IC₅₀ Example Structure (nM) 3

9.6 6

9.1 10

33 11

7.5 12

3.9Acute In Vivo Cortisone Conversion Assay

In general, compounds are dosed orally into mice, the mice arechallenged with a subcutaneous injection of cortisone at a set timepointafter compound injection, and the blood of each animal is collected sometime later. Separated serum is then isolated and analyzed for levels ofcortisone and cortisol by LC-MS/MS, followed by calculation of meancortisol and percent inhibition of each dosing group. Specifically, maleC57BL/6 mice are obtained from Harlan Sprague Dawley at average weightof 25 grams. Exact weights are taken upon arrival and the micerandomized into groups of similar weights. Compounds are prepared in 1%w-w HEC, 0.25% w-w polysorbate 80, 0.05% w-w Dow Corning antifoam#1510-US at various doses based on assumed average weight of 25 grams.Compounds are dosed orally, 200 μl per animal, followed by asubcutaneous dose, 200 μl per animal, of 30 mg/kg cortisone at 1 to 24hours post compound dose. At 10 minutes post cortisone challenge, eachanimal is euthanized for 1 minute in a CO₂ chamber, followed by bloodcollection via cardiac puncture into serum separator tubes. Once fullyclotted, tubes are spun at 2500×g, 4° C. for 15 minutes, the serumtransferred to wells of 96-well plates (Corning Inc, Costar #4410,cluster tubes, 1.2 ml, polypropylene), and the plates are frozen at −20°C. until analysis by LC-MS/MS. For analysis, serum samples are thawedand the proteins are precipitated by the addition of acetonitrilecontaining d4-cortisol internal standard. Samples are vortex mixed andcentrifuged. The supernatant is removed and dried under a stream of warmnitrogen. Extracts are reconstituted in methanol/water (1:1) andinjected onto the LC-MS/MS system. The levels of cortisone and cortisolare assayed by selective reaction monitoring mode following positiveACPI ionization on a triple quadrupole mass spectrophotometer.

Pharmaceutically acceptable salts and common methodology for preparingthem are well known in the art. See, e.g., P. Stahl, et al., HANDBOOK OFPHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH,2002); S. M. Berge, et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Sciences, Vol. 66, No. 1, January 1977. The compounds ofthe present invention are preferably formulated as pharmaceuticalcompositions administered by a variety of routes. Most preferably, suchcompositions are for oral administration. Such pharmaceuticalcompositions and processes for preparing same are well known in the art.See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro,et al., eds., 19^(th) ed., Mack Publishing Co., 1995).

The particular dosage of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof required to constitute an effective amountaccording to this invention will depend upon the particularcircumstances of the conditions to be treated. Considerations such asdosage, route of administration, and frequency of dosing are bestdecided by the attending physician. Generally, accepted and effectivedose ranges for oral or parenteral administration will be from about 0.1mg/kg/day to about 10 mg/kg/day which translates into about 6 mg to 600mg, and more typically between 30 mg and 200 mg for human patients. Suchdosages will be administered to a patient in need of treatment from oneto three times each day or as often as needed to effectively treat adisease selected from those described herein.

One skilled in the art of preparing formulations can readily select theproper form and mode of administration depending upon the particularcharacteristics of the compound selected, the disorder or condition tobe treated, the stage of the disorder or condition, and other relevantcircumstances. (Remington's Pharmaceutical Sciences, 18th Edition, MackPublishing Co. (1990)). The compounds claimed herein can be administeredby a variety of routes. In effecting treatment of a patient afflictedwith or at risk of developing the disorders described herein, a compoundof formula (I) or a pharmaceutically acceptable salt thereof can beadministered in any form or mode that makes the compound bioavailable inan effective amount, including oral and parenteral routes. For example,the active compounds can be administered rectally, orally, byinhalation, or by the subcutaneous, intramuscular, intravenous,transdermal, intranasal, rectal, ocular, topical, sublingual, buccal, orother routes. Oral administration may be preferred for treatment of thedisorders described herein. In those instances where oral administrationis impossible or not preferred, the composition may be made available ina form suitable for parenteral administration, e.g., intravenous,intraperitoneal or intramuscular.

1. A compound structurally represented by the formula:

wherein R^(0a) is -halogen; R^(0b) is —H or -halogen; R¹ is —H,-halogen, —O—CH₃ (optionally substituted with one to three halogens), or—CH₃ (optionally substituted with one to three halogens); R² is —H,-halogen, —O—CH₃ (optionally substituted with one to three halogens), or—CH₃ (optionally substituted with one to three halogens); R³ is —H or-halogen; R⁴ is —OH, -halogen, —CN, —(C₁-C₄)alkyl(optionally substitutedwith one to three halogens), —(C₁-C₆)alkoxy(optionally substituted withone to three halogens), —SCF₃, —C(O)O(C₁-C₄)alkyl, —O—CH₂—C(O)NH₂,—(C₃-C₈)cycloalkyl, —O-phenyl-C(O)O—(C₁-C₄)alkyl, —CH₂-phenyl,—NHSO₂—(C₁-C₄)alkyl, —NHSO₂-phenyl(R²¹)(R²¹),—(C₁-C₄)alkyl-C(O)N(R¹⁰)(R¹¹),

 wherein the dashed line represents the point of attachment to the R⁴position; R⁵ is —H, -halogen, —OH, —CN, —(C₁-C₄)alkyl(optionallysubstituted with 1 to 3 halogens), —C(O)OH, —C(O)O—(C₁-C₄)alkyl,—C(O)—(C₁-C₄)alkyl, —O—(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens), —SO₂—(C₁-C₄)alkyl, —N(R⁸)(R⁸), -phenyl(R²¹)(R²¹),

 wherein the dashed line represents the point of attachment to theposition indicated by R⁵; wherein m is 1, 2, or 3; R⁶ is —H, -halogen,—CN, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3 halogens); R⁷is —H, -halogen, or —(C₁-C₄)alkyl(optionally substituted with 1 to 3halogens); R⁸ is independently at each occurrence —H,—(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),—C(O)(C₁-C₆)alkyl(optionally substituted with 1 to 3 halogens),—C(O)—(C₃-C₈)cycloalkyl, —S(O₂)—(C₃-C₈)cycloalkyl or—S(O₂)—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens); R⁹ is—H or -halogen; R¹⁰ and R¹¹ are each independently —H or —(C₁-C₄)alkyl,or R¹⁰ and R¹¹ taken together with the nitrogen to which they areattached form piperidinyl, piperazinyl, or pyrrolidinyl; and R²¹ isindependently at each occurrence —H, -halogen, or—(C₁-C₃)alkyl(optionally substituted with 1 to 3 halogens), or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1,wherein R^(0a) is -fluorine and R^(0b) is —H, or a pharmaceuticallyacceptable salt thereof.
 3. A compound of claim 1 wherein R^(0a) is-fluorine and R^(0b) is -fluorine, or a pharmaceutically acceptable saltthereof.
 4. A compound of claim 1 wherein R¹ is -chlorine and R² is-chlorine, or a pharmaceutically acceptable salt thereof.
 5. A compoundof claim 4 wherein R³ is hydrogen, or a pharmaceutically acceptable saltthereof.
 6. A compound of claim 5 wherein R⁴ is

or a pharmaceutically acceptable salt thereof.
 7. A compound of claim 5wherein R⁴ is

and R⁶ is —H, or a pharmaceutically acceptable salt thereof.
 8. Acompound of claim 7 wherein R⁵ is chlorine or fluorine, or apharmaceutically acceptable salt thereof.
 9. A compound that is(R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one,or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition which comprises a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 11.A method of selectively reducing the glycemic level in a mammalcomprising administering to a mammal in need thereof an 11-betahydroxysteroid dehydrogenase 1 inhibiting dose of a compound or salt asdescribed in claim
 1. 12. A method for treating type 2 diabetes in apatient in need thereof which comprises administering to said patient aneffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 13. A method for treating type 2 diabetes whichcomprises administering to a patient in need thereof an effective amountof a pharmaceutical composition of claim
 10. 14. A compound of claim 1selected from the group consisting of:(R)-3-(2,6-Dichloro-4-hydroxy-benzyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one;3′,5′-Dichloro-4′-[(R)-1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylicacid methyl ester;(R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one;(R)-1-(4,4-Difluoro-cyclohexyl)-3-(3,5,4′-trichloro-biphenyl-4-ylmethyl)-pyrrolidin-2-one;(R)-3-(3,5-Dichloro-4′-trifluoromethoxy-biphenyl-4-ylmethyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one;(R)-3-[2,6-Dichloro-4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one;3′,5′-Dichloro-4′-[(R)-1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylicacid;(R)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one;3-(2,6-Dichloro-4-methoxy-benzyl)-trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one;3-(4-Bromo-2-chloro-benzyl)-trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one;3-(4-Bromo-2-chloro-benzyl)-cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one;3-(2,6-Dichloro-4-pyridin-3-yl-benzyl)-cis-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one;3-(2,6-Dichloro-4-pyridin-3-yl-benzyl)-trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one;3-(4-Bromo-2-chloro-benzyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one;and3-(2,6-Dichloro-4-pyridin-3-yl-benzyl)-1-(4,4-difluoro-cyclohexyl)-pyrrolidin-2-one;or a pharmaceutically acceptable salt thereof.